FR2480284A1 - ANTIHYPERTENSIVE AMINES, PROCESS FOR THEIR PREPARATION AND ANTIHYPERTENSIVE COMPOSITIONS CONTAINING THEM. - Google Patents

Abstract

THE INVENTION RELATES TO COMPOUNDS OF FORMULA (CF DRAWING IN BOPI) IN WHICH R REPRESENTS A HYDROGEN ATOM, AN ALKYL OR ARYL GROUP, A HALOGEN ATOM, A LOWER ALCOXYL GROUP, NITRO, AMINE, ALKYLANOMERCAPTO, CYCLING , CARBALCOXYL, SULFAMYL, TRIFLUOROMETHYL, HYDROXYL, ACYLOXYL, METHANESULFONYL, ALKYLAMINE, OR ACYLAMINE, R AND R EACH REPRESENT AN ALKYL GROUP, EACH OF THE ALKYL GROUPS, EACH OF THE ALKENYL GROUPS OF ALKENYL AND ATOMADONYL, ALKYLAMINE PLUS 10, ALKYLAMINE, AND ACBADONYL, PLUS ACBALYL, AND ACBDONYL, ALKENYL, ACB. OF PHARMACEUTICALLY ACCEPTABLE AND NON-TOXIC ACID OF THESE COMPOUNDS. THESE COMPOUNDS SHOW ANTIHYPERTENSIVE PROPERTIES.

Description

- 1 -

  The present invention relates to novel antihypertensive agents and, more particularly, to certain novel substituted 1,4-dihydropyridines having useful antihypertensive activity. 1,4-dihydropyridines are known to be substituted and

  they are described in the literature as vasodilat-

  tors. 1,4-Dihydropyridines having a vasodilating activity are characterized by the presence of alkyl substituents at the 2- and 6-positions of the pyridine ring

  and carbalkoxyl groups in positions 3 and 5, usually

  Alternatively, with a substituent, most commonly phenyl or substituted phenyl, at the 4-position. To increase the solubility of these compounds in water, M. Iwanami et al. (Chem Pharm Bull., 27 (6) 1426 & 1440 (1979)) have described the effect obtained when the nitrogen of the pyridine ring carries, inter alia, as substituents, aminoalkylene groups such as pyrrolidinoethyl and dimethylaminoethyl. Thus, the solubility in water of compounds such as

  that the diethyl-1,4-dihydro-4- (3-nitrophenyl) -2,6-di-

  methyl-1- (2-pyrrolidinoethyl) aminoethyl, as well as their potency as vasodilators, but it appeared that these compounds had a lower potency than known compounds such as the corresponding ethoxymethyl derivative. JA 70767/76 discloses, as antihypertensives and vasodilators, 1,4-dihydropyridines corresponding to the formula s P H R'02C C2Re

R R

- A - N

- R '*'

  in which R is an alkyl group, P is a monosubstituted or disubstituted phenyl, pyridyl, furyl or thienyl group, the substituents of which are hydrogen atoms or

- - 2 -

  Halogen, or -CN, -NO2, -NH2, -N (CH 3) 2 'carboxyl, methoxyl, ethoxyl, butoxyl, sulfonyl, methylsulfonyl or acetyl groups, R1 is an alkyl, aralkyl or methyl group; ethyl, isopropyl, tertiary butyl, ethoxyethyl, benzyl, phenethyl or 4-methoxybenzyl, A is an alkylene group and R "and R '' each represent an alkyl group or form, together with the nitrogen atom to which

  they are attached, a pyrrolidine nucleus.

  U.S. Patent 3,441,648 discloses antihypotensive 1-4-dihydropyridines having the formula: o13

R OOC COOR

2 2

R1 R

R4

  wherein R 1 and R 2 are lower alkyl groups containing 1 to 6 carbon atoms, R 3 is phenyl, halophenyl, dihalophenyl, lower alkylphenyl,

  bis- (lower alkyl) -phenyl, tris (lower alkyl) -

  phenyl, (lower alkoxyl) -phenyl, bis- (lower alkoxyl)

  phenyl, tris- (lower alkoxyl) -phenyl, trifluoromethylphenyl, benzyl, styryl, furyl, thienyl, pyridyl or pyrrolidyl, the lower alkyl and lower alkoxyl groups containing 1 to 4 carbon atoms, and R4 is an atom of hydrogen or a lower alkyl group

containing 1 to 6 carbon atoms.

  The novel compounds of the present invention are N-morpholinoalkyldihydropyridines having the formula: Ar RiO2C Co2R1

12 R R

Z - ..

Z N 0

R

  Wherein Ar is a heteroaryl, cycloalkyl group of 3 to 7 carbon atoms, naphthyl, indanyl, indenyl, tetrahydronaphthyl or a radical of the formula s Rs R7 R6

  wherein R5, R6 and R7 each independently represent

  hydrogen, alkyl or aryl, halogen, lower alkoxy, nitro, alkylmercapto, cyano, carboxyl, carbamoyl, sulfamyl, trifluoromethyl, hydroxyl, acyloxyl, methanesulfonyl, alkylamine or acylamine, R5 and R 6 being together capable of forming a methylenedioxy group, Z is an alkylene group containing about 1 to 5 carbon atoms in the main chain, each of R 1 is independently a hydrogen atom or an alkyl or alkoxyalkyl group, with the proviso that a single R 1 may represent a hydrogen atom, R 2 is a lower alkyl group, R 3 and R 4 independently represent a hydrogen atom or a lower alkyl group, as well as the pharmaceutically acceptable and non-toxic acid addition salts formed by these compounds. Each of the alkyl, acyl and alkoxyl groups contains at most about 10 carbon atoms and preferably at most 6 carbon atoms. The substituent Z contains at most about carbon atoms in the main catena, ie the right carbon ring between the terminal valences, but it can be branched, that is to say that the main chain may carry methyl and ethyl substituents. Thus, the alkylkne Z chain may contain in total more than 5 carbon atoms, preferably without

exceed about 8.

  Heteroaryl group herein denotes any heterocyclic structure containing at least one of the 0, S and N heteroatoms. These compounds include thiophene, furan, pyridine, thiazole, pyrimidine, pyrrole, benzofuran, quinoline, benzothiophene and substituted heterocycles The preferred compounds are those whose hydrocarbyl radicals contain at most about 7 carbon atoms when they are aliphatic and at most about carbon atoms when aromatic, as

  phenyl, tolyl and naphthyl groups.

  Particularly preferred compounds of the invention are those wherein Z is -CH 2 CH 2 - and Ar is trifluoromethylphenyl, especially 2-trifluoromethylphenyl. The novel compounds of the invention can be prepared by known methods, starting from known initial compounds, as described, for example, in the cited literature.

  upper. The following preparation process is particularly

  Conveniently s Ar 3 RO2C Co2 + X - Z- -4 Formula I

II III R4

  The reaction can be carried out in a solvent in the presence of sodium hydride or any alkali metal hydride or alkoxide, as is common in condensation reactions. The reaction is carried out in two stages, the first being metallation with the alkaline compound and the second with the halide containing X, which is usually a chloride. Hydrides are convenient because the progress of the metallation reaction can be monitored by observing the evolution of hydrogen. The metallation step is normally conducted at room temperature. Then, the mixture is heated to elevated temperature, for example in a steam bath at about 100 ° C, depending on the boiling point of the selected solvent, and then the halide compound is added, usually in controlled amounts, dropwise and once the addition is complete, the mixture is digested by heating at the elevated temperature. The product is then obtained in the usual manner, for example by cooling to cause the precipitation or evaporation of the solvent and to obtain the product as a residue. An alternative process for the preparation of new

  compounds of the invention consists in condensing an N- (aminoal-

  kyl) -morpholine with ArCHO and a carbonyl compound to provide the remainder of the dihydropyridine ring of formula

  R2COCHa R1. Two moles of the carbonyl compound react

  on one mole of morpholine and one mole of ArCHOe. The reaction is usually carried out in a solvent, preferably miscible with water, for example an alcohol such as ethanol, methanol or propanol, preferably at reflux temperature. The reaction is usually complete in about 6 to 24 hours, about 8 to 15 hours

being preferential.

  The product is obtained by removing the solvent, for example by distillation or by dilution with water. The product, usually oily, is then extracted with a suitable solvent, such as ethyl acetate, and

  it is recovered in the extract in the usual way.

  By applying this method, it is possible to prepare various novel N-morpholinoalkyl-1,4dihydropyridines corresponding to the following formula:

R5 R7

% R I6 R102C 1- 2

R2 N O

2 2 z R1N%

Z 1 R2 R5

i 2i 6 8

CHE3 CH3 C2H5 H H H

  cHOE3 CE3 2.5 C H CH2CH2 CH3 C2% H a

CH (CH 3) CH 2 C 2 H 5 C H H C

  CH2 2 2 3 3 7 Cl H CH2COU OH3 C2H5 aH H 2

C2CH2 CE3 2 "5 CH E

CH2CH2 C3H7C3HH CF3

(2) 36132 5 HCOO H

CH2CH3) CH3 C2H5H3a

2 (C2) 5CH43C25OOH H C

<CE2CH2 CH7 CH3HH3H

CHCH-H 2 3 2 C5 H CHCE3

CH (CH3) CH3 C2H5H OCH3C

CH2CH2 CH3 C2H5 HH CHO

CH2U CH3 CH HH CCCH3) 3

c2ce2 3-4 25 o

CE (CH3) CE2OH3 2A S C6 H

H HH 6

CH2CH2 OH3 C2OH

2 2CH 3C25

(%) 5cH3c2as e ci3ci

2ce2ce2 c% 3 COH5 Cl Cl.

CH2CH2 CH3. 2s 5 () - 7-

R1 R2 R5

6 R7

CH2CH2

CH2CE2

%%

CH2CH2

2

CH2CH2

CH2cH2 CH2C2

CH2CH2

CH2c 2 ce22cH2

CH2CH2

CH2CH2

CH2CH2

c22 SCH C

CE2CH2

C2î2

CH2C "2

CH2CEI2

CH2CH2

CR2C% 2

CH2c2

C2C2

CH-2CH2

CH2CH2

  ## STR1 ## wherein: C2H5 C25 C2H5 C2H5 c2H5 C2H5 C2H5 C25 C2H5 C5 C2H5 C25 C2H5 C25 C25 C25 C2H C25 2H5 C1 Cl OCH3 HHHHHH a HHHH NO2 HHHH OCH3 HH OCH3 OO3 H OCR3 HHHHHH CH C3 HH CH HH CH H CL H OH CF3 OCM3 COOH H O03 HHHHH C1 C1

CH2 = CH-CH2

  aH H H H c H3 O C H H H H H H H H H H H O CRE

CH2 = CH ,,, CH2-

COO3

COOCH 3

- (CH2) 4-

  The compounds of the invention are characterized by high antihypertensive activity with little or no

  harmful side effects. For example, determinations

  toxicity in mice gave an LD of

  320 mg / kg (intraperitoneal route) for 144-dihydro-4- (2-

  trifluoromethylphenyl) -26-dimethyl-l- (2-morpholinoethyl) -

  Diethyl pyridine-3,5-dicarboxylate, while the corresponding 1 (2-pyrrolinoethyl) compound had an LD50 of 74 mg / kg (intraperitoneal route). The first compound does not give tachycardia in the mouse at 30 mg / kg (bw), whereas the second cause of the

  tachycardia at 1 mg / kg (intraperitoneal route).

  The novel heterocyclic compounds according to the invention are therapeutically useful as such or else

  use them in the form of salts, given their basic nature.

  Thus, these compounds form salts with a wide variety of inorganic and organic acids, including non-toxic, pharmaceutically acceptable acids. The pharmaceutically acceptable acid salts are of course useful in the preparation of compositions which it is desired to render water-soluble. The pharmaceutically unacceptable acid salts are particularly useful in the isolation and purification of novel compounds. Therefore, all the acid salts of the novel compounds are contemplated by the invention. The pharmaceutically acid addition salts

  acceptable are particularly useful in therapeutics.

  They include salts of mineral acids such as

  hydrochloric acid, hydroiodic acid, hydrobromic acid, phospho-

  methacrylic, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, mandelic, glycolic, gluconic, succinic, nicotinic acids,

  salts of arylsulphonic acids such as p-toluene

  sulfonic acid, etc. The pharmaceutic acid addition salts

  unacceptable, while not being useful in

  therapeutic, are useful for the isolation and purification of

  new substances. In addition, they are useful

  to the preparation of pharmaceutically acceptable salts.

  In this group, the most common salts are those

  are formed with hydrofluoric and perchloric acids.

  The hydrofluorides are particularly useful in the preparation of pharmaceutically acceptable salts, for example hydrochlorides, by dissolution in the acid.

  hydrochloric acid and crystallization of the hydrochloride formed.

  Perchloric acid salts are useful for the purification and crystallization of new products. The compounds of the invention have lower acute toxicity and give less tachycardia than the closest analogs structurally described. As therapeutic agents, the compounds

  heterocyclic compounds according to the invention are particularly

  useful as antihypertensives. Therapeutic agents

  The invention may be administered in isolation or in combination with pharmaceutically acceptable carriers the proportion of which is determined by the solubility and chemical nature of the compound, the chosen route of administration and the usual pharmaceutical practice. For example, they can be administered orally in the form of tablets or capsules containing excipients such as starches, lactose, certain types of clay, etc. They can be administered orally in the form of solutions which may contain dyes and arteries, or they may be parenterally injected, i.e. intramuscular, itraveinous or subcutaneous. For parenteral administration, they can be used in the form of a sterile solution containing other solutes, for example, enough physiological saline to make the solution isotonic. The doctor will determine the most appropriate dosage of the therapeutic agents according to the invention, since it varies according to the mode of administration and the compound

  chosen and that, moreover, it varies according to the patient to be treated.

  The physician will generally wish to start the treatment with small dosages, substantially below the optimal dose of the compound, and increase the dosage in small increments until the optimum effect under the circumstances is achieved. It will usually be found that,

- 10 -

  when the composition is administered orally, larger amounts of the active agent are required to give the same effect as a smaller amount administered parenterally. The compounds are useful in the same way as other antihypertensives and the dosage level is of the same order of magnitude as for these other therapeutic agents in general. The therapeutic dosage will generally be from 10 to 750 mg / day and more, although it may be administered in several different dosage units. Tablets containing 10 & 250 mg of agent

  active are particularly useful.

  The following examples further illustrate the invention.

EXAMPLE 1

  1,4-Dihydro-4- (2-trifluoroethylphenyl) -2,6-dimethyl-1- (2-

  diethyl morpholinoethyl) -pyridine-3,5-dicarboxylate.

  To a slurry of 2.6 g (55 mol) of sodium hydride (50:50 oily dispersion) in 50 ml of dry distilled dimethylformamide, under a nitrogen atmosphere, a

  solution of 19.9 g (50 mmol) of 1,4-dihydro-4- (2-trifluoro-

  diethylmethylphenyl) -2,6-diethylpyridine-3,5-dicarboxylate in 125 ml of dimethylformamide. Once the evolution of hydrogen has ceased, the mixture is heated in a water bath for 1/2 hour and

  drop a solution of 8.1 g (60 muol) of bN- (2-chloroethyl) -

  morpholine in 200 ml of toluene. Stir the mixture

between 110 and 115C for 4 hours.

  The mixture was cooled, filtered in vacuo and the filtrate concentrated in vacuo. The brown paste is taken up in refluxing hexane and allowed to crystallize. Recrystallization in hexane gives

4.3 g of a beige solid.

EXAMPLE 2

  1,4-Dihydro-4- (2-trifluoroethylphenyl) -2,6-dimethyl-1- (2-

  diethyl morpholinoethyl) -pyridine-3,5-dicarboxylate.

  In a 100 ml round-bottomed reactor, 3.0 g (17.5 mmol) of otrifluoromethylbenzaldehyde and 5 ml are added.

- 11 -

  (39 mmol) ethyl acetoacetate. The mixture is stirred and 20 ml of ethanol are added. To the stirred mixture was added 2.86 g of N- (2-aminoethyl) morpholine. We heat the

  overnight under reflux with a layer of nitrogen.

  The mixture is treated as follows: The cooled mixture is poured into an excess of citric acid solution at 1 mol / l and extracted with ethyl acetate. The ethyl acetate phase is separated, washed crosswise with 1 mol / l sodium bicarbonate solution and finally with brine. The ethyl acetate phase is separated off, dried over magnesium sulphate

  it is clarified and concentrated to obtain an oil.

  The oil is chromatographed on silica gel to obtain

the desired product.

- 12 -

Claims (10)

  1.- Compounds corresponding to the formula s Ar R10 2C CO2R, R-2 4 N> 2 R3   in which Ar is a heteroaryl, cycloalkyl group of 3 to 7 carbon atoms, naphthyl, indanyl, indenyl, tetrahydronaphthyl or a radical corresponding to the formula: R R6 7   wherein R5, R6 and R7 each independently represent   hydrogen, alkyl or aryl, halogen, lower alkoxy, nitro, amine, alkylmercapto, cyano, carboxyl, carbalkoxyl, sulfamyl, trifluoromethyl, hydroxyl, acyloxyl, methanesulfonyl. alkylamine or acylamine, R5 and R6 together may form a methylenedioxy group, Z is an alkylene group containing about 1 to 5 carbon atoms in   the main chain, each of the R1 represents independently   hydrogen or an alkyl or alkoxyalkyl group, with the proviso that only one R may represent a hydrogen atom, R2 is a lower alkyl group, R3 and R4 independently represent a hydrogen atom or an alkyl group; lower, each of the alkyl, acyl and alkoxyl groups contains at most 10 carbon atoms, as well as the pharmaceutically acid addition salts   acceptable and non-toxic formed by these compounds.   2. A compound according to claim 1, characterized - 13 -   in that the alkyl, alkoxyl and acyl groups   contain up to 6 carbon atoms.   3. A compound according to claim 2, characterized in that Ar is a monosubstituted phenyl group and Z is -CH 2 -CH 2 -O 4. A compound according to claim 1, characterized in that the heteroaryl group is a group   thienyl, furyl, thiazolylpyridyl or quinolyl.   5. A compound according to claim 2, characterized   in that Ar is a trifluoromethylphenyl group.   6. A compound according to claim 2, characterized in that Ar is a trifluoro-methylphenyl group. and Z is -C 2 -CH 2.   7. 1,4-Dihydro-4- (2-trifluoromethylphenyl) -2,6-dimer   diethyl ethyl-1- (2-morpholinoethyl) -pyridine-3,5-dicarboxylate 8e- A pharmaceutically acceptable, non-toxic addition salt formed by the compound of claim 7 with an acid.   9. Antihypertensive composition comprising a compound according to claim 1.   o- antihypertensive compounds, characterized in that they meet the formula: l2 OR I Ir R22 H2C-CH2-N O   in which R5 represents a hydrogen atom, an alkyl or aryl group, a halogen atom, a group - 14 -   lower alkoxyl, nitro, amine, alkylmercapto, cyano, carboxyl, carbalkoxyl, sulfamile, trifluoromethyl, hydroxyl, acyloxyl, methanesulfonyl, alkylamine or acylamine, R1 and R2 each represent an alkyl group, each alkyl, alkoxyl and acyl group containing not more than 10 carbon atoms, as well as pharmaceutically acceptable and non-toxic acid addition salts of these compounds.   11. Compounds according to claim 10, characterized in that R1 is an ethyl group, R2 is a methyl group, R3 and R4 are hydrogen atoms and R5 a trifluoromethyl group.   12. A process for preparing a compound according to one of   Claims 1 to 8, 10 and 11, characterized by the   causes a compound of formula Ar to be condensed O2C -CO2R R R   II O with a compound of formula 2 R3 X-Z-N O III R4   under conditions known in themselves.   13. A process for preparing a compound according to one of   Claims 1 to 8, 10 and 11, characterized in that   N- (aminoalkyl) -morpholine is condensed with an aldehyde of formula ArCHO and a carbonyl compound of formula R2COCH2CO2R, the symbols Ar, R and R2 being as previously defined, under conditions known per se.